Glial cells, particularly microglia, have been implicated in the progression of Alzheimer's disease based their ability to release inflammatory substances and engage in phagocytosis. One aspect of microglial phagocytosis that has garnered significant attention is uptake of the amyloid beta peptide, or Abeta. The high levels of extracellular amyloid found in the Alzheimer's brain suggest that if phagocytosis of Abeta does occur in vivo, it is in large part insufficient to compensate for amyloid deposition. Internalization of Abeta microglia has therefore been viewed as a target for therapeutically altering the balance between generation and removal of Abeta to favor decreased deposition into senile plaques. However, this hypothesis presumes that microglia possess the capacity to break down internalized peptide. It is known that interactions of phagocytic cells with noningestable/undegradable structures leads to the phenomenon of "frustrated phagocytosis" with concomitant release of inflammatory (and neurotoxic) compounds. In addition, if microglia cannot degrade internalized peptide, therapeutic attempts to augment microglial phagocytosis of Abeta would likely heighten inflammatory neuronal damage. The proposed experiments will investigate these hypotheses by 1) evaluating the ability of microglia to phagocytose and degrade Abeta, 2) determining the effects of Abeta phagocytosis on microglial viability, and 3) characterizing the release of inflammatory cytokines and reactive oxygen and nitrogen free radicals by microglia in response to internalized Abeta. Results from these studies will provide the basis for further studies to assess the role of, and potentially intervene in, glial function in AD.